Predictive value of heterogeneous HDL subfractions

05/10/2015

In the MESA cohort, smaller HDL particles were inversely related to a novel composite of serious non-CVD, noncancer inflammation-related diseases.

High‐Density Lipoprotein Subclasses and Noncardiovascular, Noncancer Chronic Inflammatory‐Related Events Versus Cardiovascular Events: The Multi‐Ethnic Study of Atherosclerosis
Literature - Duprez DA et al., JAHA 2015


Duprez DA, Otvos J, Tracy RP, et al.
J Am Heart Assoc. 2015;4:e002295. Originally published September 14, 2015. doi: 10.1161/JAHA.115.002295

Background

The inverse relationship between HDL-c levels and coronary heart disease (CHD) was thought to be explained by an antiatherosclerotic effect of reverse cholesterol transport [1]. Randomised clinical trials assessing means to increase HDL-c have yielded disappointing results [2,3].
HDL particle subtypes differ in lipid and protein content, with protective and nonprotective components not reflected by HDL-c [4]. HDL particles may also be involved in inflammation; HDL particles have been described to inhibit vascular inflammation [5], and to have antioxidant [6] and antithrombotic properties [7], and to suppress the production and mobilisation of monocytes and neutrophils from bone marrow [8].
This study examined HDL particles of small (HS-P), medium (HM-P) and large (HL-P) diameter plus HDL-c in relation to CV disease, while adjusting for other blood lipid variables and 6 lipoprotein particle subclass variables of the LDL family. The study originates from the hypothesis that smaller HDL particles are inversely related to non-CVD, noncancer chronic inflammation-related disease (ChrIRD) death and hospitalisation, as well as CVD. Data of the Multi-Ethnic of Atherosclerosis (MESA) cohort of people initially free of overt clinical CVD [9] were used.

Main results

  • HL-P correlated closely with HDL-c (r=0.89). HS-P and HM-P were also highly correlated (R=-0.62). HL-P had strong and opposing correlations with large LDL particles (r=0.5) and small LDL particles (r=-0.67).
  • A pattern of decreasing correlation was seen across HS-P, HM-P and HL-P, with for example small LDL particles, while the corresponding correlations were increasing for HDL-c and large LDL particles.
  • Adding the pair of HS-P and HM-P to a covariate-adjusted model predicted ChrIRD to a similar extent as HL-P and HDL-C or HS-P and HM-P did for CVD and CHD.
    When LDL variables were added to the model, the greatest improvement in prediction was for ChrIRD by using the pair HS-P and HM-P. The predictive value of this pair was less strong for CVD.
  • Outcome incidence densities per 100 participants followed for 10.1 years, in the most adjusted model, decreased with increasing HMS-P (sum of HM-P plus HS-P) for ChrIRD, and CVD and CHD outcomes.
    For instance, the relative risk of ChrIRD deaths per 1 SD of HMS-P was 0.81 (95%CI: 0.71-0.93, P for trend: 0.003). Similarly, significantly reduced risks were also seen for ChrIRD hospitalisation and for infectious disease death or hospitalisation.

Conclusion

These findings show that the smaller HDL particles, namely HMS-P, are significantly predictive for non-CVD, non-cancer ChrIRD, and to a lesser extent for fatal and nonfatal CVD in patients of the MESA cohort, who were initially free of overt CVD, even after adjusting for other risk factors and variables in the HDL and LDL lipoprotein families. While the pair of correlated HL-P and HDL-c particles was associated to CVD in unadjusted analyses, it was no longer predictive when the LDL family was entered in the model.
The constant dynamic remodelling of heterogeneous HDL subfractions may have functional implications. The current data may indicate that it is beneficial to have more smaller HDL particles. The observation that HMS-P better predicts non-CVD and noncancer ChrIRD than CHD may point towards an anti-inflammatory effect of HDL particles.


Find this article online at JAHA

References

1. Rye KA, Barter PJ. Cardioprotective functions of HDL. J Lipid Res. 2014;55:168–179.
2. Barter PJ, Caulfield M, Eriksson M,et al; ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–2122.
3. Schwartz GG, Olsson AG, Abt M, et al; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–2099.
4. Rosenson RS, Brewer HB Jr, Chapman MJ, et al. HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. Clin Chem. 2011;57:392–410.
5. Duprez DA, Kuller LH, Tracy R, et al; INSIGHT SMART Study Group. Lipoprotein particle subclasses, cardiovascular disease and HIV infection. Atherosclerosis. 2009;207:524–529.
6. Camont L, Lhomme M, Rached F, et al. Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, antiinflammatory, and antiapoptotic functionalities. Arterioscler Thromb Vasc Biol. 2013;33:2715–2723.
7. Mineo C, Deguchi H, Griffin JH, Shaul PW. Endothelial and antithrombotic actions of HDL. Circ Res. 2006;98:1352–1364.
8. Westerterp M, Bochem AE, Yvan-Charvet L, et al. ATPbinding cassette transporters, atherosclerosis, and inflammation. Circ Res. 2014;114:157–170.
9. Bild DE, Bluemke DA, Burke GL, et al. Multi-Ethnic Study of Atherosclerosis: objectives
and design. Am J Epidemiol. 2002;156:871–881.

Register

We're glad to see you're enjoying PACE-CME…
but how about a more personalized experience?

Register for free